Abstract 1093: Measuring and inhibiting purine metabolism in patients with glioblastoma
Authors: Yoshie Umemura, Andrew J. Scott, Wajd Al-Holou, Anjali Mittal, Weihua Zhou, Kari Wilder-Romans, Jie Xu, Nathan Qi, Maureen Kachman, Michelle Kim, Larry Junck, Denise Leung, Nathan Clarke, Jason Heth, Bo Wen, Amit Pai, Vijay Tarnal, Deepak Nagrath, Theodore Lawrence, Costas A. Lyssiotis, Daniel R. Wahl
Journal: Cancer Research (2023)

Abstract Introduction: We have previously found that purine metabolism is an important metabolic mediator of treatment resistance in glioblastoma (GBM). Mycophenolate mofetil (MMF), an inhibitor of purine synthesis, synergizes with radiation and temozolomide in mouse models of GBM. No measurements of purine synthesis have been performed in human cancer patients, nor has the purine inhibitor MMF been used clinically for patients with GBM. Methods: We infused clinical-grade 13C6 glucose into patients undergoing craniotomy for presumed GBM and used mass spectrometry to measure carbon incorporation into purines in cortex and disparate tumor regions. We are conducting a phase 0/1 trial (NCT04477200) to determine the safety and potential efficacy of the purine inhibitor MMF in patients with GBM. In the phase 0 arm, patients with recurrent GBM needing tumor re-resection receive MMF for one week prior to surgery and tumor and brain tissue is analyzed by mass spectrometry to determine drug concentrations and target engagement. In the phase 1 portions, patients (age &amp;gt;18, KPS ≥ 60) with recurrent GBM are treated with MMF and a second course of radiation while patients with newly diagnosed GBM are treated with radiation (RT), temozolomide (TMZ) and MMF followed by cyclic MMF and TMZ. A TITE-CRM algorithm is employed to dose-escalate MMF (range 500-2000 mg BID) and determine its maximum tolerated dose in combination with RT and/or TMZ. Results: Stable isotope tracing has been performed on 8 patients with suspected GBM. Purine synthesis was increased in tumor tissue compared to normal cortex in all patients, with most patients having 10-30-fold increased purine labeling in tumor. We have enrolled 8 patients on our phase 0 peri-surgical study and all had active concentrations of mycophenolic acid (the active metabolite of MMF) in enhancing and non-enhancing GBM tissue. We have enrolled 28 evaluable phase 1 patients (13 recurrent, 15 new). No dose-limiting toxicities have been observed with MMF (1000-2000 mg BID) in combination with re-irradiation or cyclic TMZ. In concurrent chemoradiation with MMF, we have observed two dose limiting grade 3 toxicities at 2000 mg, both improved with treatment break. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 patients is 15.6 months, which compares favorably with typical survival time of 8-10 months in this population. In the newly diagnosed cohort, median survival is not yet reached, but 14 of 15 patients are alive and without progressive tumor. Conclusions: Glucose-derived purine synthesis is elevated in human GBM compared to cortex, which could provide a favorable therapeutic index for purine synthesis inhibition. The purine synthesis inhibitor MMF achieves active concentrations in human GBM, is reasonably well tolerated in combination with standard GBM treatments, and is associated with promising preliminary clinical outcomes. Citation Format: Yoshie Umemura, Andrew J. Scott, Wajd Al-Holou, Anjali Mittal, Weihua Zhou, Kari Wilder-Romans, Jie Xu, Nathan Qi, Maureen Kachman, Michelle Kim, Larry Junck, Denise Leung, Nathan Clarke, Jason Heth, Bo Wen, Amit Pai, Vijay Tarnal, Deepak Nagrath, Theodore Lawrence, Costas A. Lyssiotis, Daniel R. Wahl. Measuring and inhibiting purine metabolism in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1093.